Taboada M, Estany-Gestal A, Fernández J
… +34 more, Dos Santos L, Barreiro L, Williams K, Cardalda-Serantes B, López C, Méndez M, Rodríguez-Yáñez M, Otero P, Naveira A, Caruezo V, Veiras S, San Luis E, Diaz-Vieito M, Arias-Rivas S, Santamaría-Cadavid M, Rodríguez-Castro E, Mosquera A, Castiñeiras JA, Vázquez F, Blanco M, Taboada JL, Muniategui I, Ferreiroa E, Cariñena A, Tubio A, Campaña O, Selas S, Aneiros F, Martínez A, Eiras M, Costa J, Prieto JM, Álvarez J, Seoane-Pillado T
JAMA Neurol
· 2026 May · PMID 41910960
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IMPORTANCE: The optimal timing of extubation after endovascular thrombectomy performed under general anesthesia for patients with acute ischemic stroke remains uncertain. OBJECTIVE: To evaluate whether early extubation (...IMPORTANCE: The optimal timing of extubation after endovascular thrombectomy performed under general anesthesia for patients with acute ischemic stroke remains uncertain. OBJECTIVE: To evaluate whether early extubation (<6 hours) compared with delayed extubation (6-12 hours) after successful thrombectomy under general anesthesia improves 90-day functional outcomes. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted at a single tertiary academic referral center from April 2023 to June 2025 with 90 days of follow-up. Participants were adults (age ≥18 years) with acute ischemic stroke due to anterior circulation large-vessel occlusion who underwent successful endovascular thrombectomy under general anesthesia. INTERVENTIONS: Participants were randomly assigned (1:1) to receive early (<6 hours) or delayed (6-12 hours) extubation following thrombectomy. MAIN OUTCOMES AND MEASURES: The primary outcome was functional independence at 90 days (as indicated by a modified Rankin Scale [mRS] score of 0-2). Secondary outcomes included the ordinal distribution of mRS scores, length of hospital stay, respiratory and procedure-related complications, and 90-day mortality. RESULTS: Of 312 patients assessed, 174 were randomized, 87 to receive early extubation and 87 to delayed extubation. Ninety-eight patients (56.3%) were women and 76 (43.7%) were men; the median (IQR) age was 76 (69-86) years. Functional independence at 90 days occurred in 41 of 86 patients (47.7%) in the early group and 39 of 85 (45.9%) in the delayed group (risk ratio [RR], 1.04; 95% CI, 0.76 to 1.43). The ordinal analysis of mRS scores showed no significant difference between groups (generalized odds ratio, 0.93; 95% CI, 0.66 to 1.31). Median (IQR) length of hospital stay was 6 (3-9.5) days in the early group and 6 (4-10) days in the delayed group (median difference, 0.0 days; 95% CI, -1.81 to 1.81). The incidence of pneumonia was 19 patients (21.8%) in the early group and 26 patients (29.9%) in the delayed group (RR, 0.73; 95% CI, 0.44 to 1.22), and reintubation occurred in 4 patients (4.6%) vs 2 patients (2.3%), respectively (RR, 2.00; 95% CI, 0.37 to 10.9). Mortality at 90 days was 20 of 86 patients (23.3%) in the early group vs 19 of 85 patients (22.4%) in the delayed group (RR, 1.04; 95% CI, 0.60 to 1.81). CONCLUSIONS AND RELEVANCE: Among patients with acute ischemic stroke undergoing successful thrombectomy under general anesthesia, early extubation (<6 hours) did not improve functional independence compared with delayed extubation (6-12 hours). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05847309.
Boudot de la Motte M, Gavoille A, Papeix C
… +46 more, Audoin B, Ayrignac X, Bourre B, Ciron J, Cohen M, Collongues N, Laplaud DA, Maillart E, Michel L, Pique J, Ruet A, Thouvenot E, Zephir H, Aboab J, Moreau T, Mathey G, Froment C, Mélé N, Casez O, Branger P, Kerschen P, Al Khedr A, Maurousset A, Berger E, Moulin M, Clavelou P, Lommers E, Sarov M, Cantagrel P, Megherbi H, Hankiewicz K, Ahle G, Magy L, Giannesini C, Cabasson S, Tourniaire P, Montcuquet A, Creange A, Pegat B, Delpont B, Casey R, Bonjour M, Benyahya L, Deschamps R, Marignier R, NOMADMUS group
IMPORTANCE: Therapeutic deescalation strategies are increasingly considered in demyelinating diseases to mitigate the risks associated with prolonged immunosuppression. The impact of treatment discontinuation in myelin o...IMPORTANCE: Therapeutic deescalation strategies are increasingly considered in demyelinating diseases to mitigate the risks associated with prolonged immunosuppression. The impact of treatment discontinuation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is not established. OBJECTIVE: To assess the relapse risk following treatment discontinuation in adult patients with MOGAD and to evaluate factors associated with disease reactivation. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study including 41 centers was conducted using the French NOMADMUS database. Adult patients with MOGAD diagnosed between January 2013 and April 2024 were included. Data were extracted on July 1, 2024. A total of 1047 patients with MOGAD were screened, and 705 patients fulfilled the inclusion criteria. Among them, 319 (45.2%) received at least 1 maintenance therapy. EXPOSURE: All instances of treatment discontinuation were collected and categorized according to their underlying reasons. Only discontinuations that were scheduled or related to adverse events were analyzed. MAIN OUTCOMES AND MEASURES: Time to first relapse was estimated using Kaplan-Meier survival curves, and differences between groups were assessed using the log-rank test. RESULTS: A total of 83 patients (median [IQR] age, 42.7 [28.9-53.3] years; 52 [63.7%] female) discontinued either oral immunosuppressants (azathioprine or mycophenolate mofetil) or rituximab in 60 (72.1%) and 23 (27.7%) individuals, respectively. Discontinuations were scheduled (n = 54 [65.1%]) or related to adverse events (n = 29 [34.9%]). After discontinuation, 7 patients relapsed, with a median (IQR) time to relapse of 0.5 (0.1-1.4) years. The Kaplan-Meier estimated cumulative incidence of relapse at 1 year after discontinuation was 8.7% (95% CI, 1.0-15.9). Severity of relapses was mild, with a median (IQR) change in the Expanded Disability Status Scale score of 0 (0-1) points. Factors associated with an increased relapse risk were a treatment duration of less than 1 year (7 relapses [19.4%] vs 0 relapses; log-rank P = .002) and a time since last relapse of less than 2 years (7 relapses [15.9%] vs 0 relapses; log-rank P = .01). CONCLUSIONS AND RELEVANCE: The low risk of disease reactivation found in this study suggests that discontinuing treatment may be considered in selected adult patients with MOGAD. Future clinical trials are necessary to confirm these results and establish guidelines in this situation.
Zhang R, Vidoni E, Vongpatanasin W
… +13 more, Kerwin DR, Cullum CM, Rossetti H, Stowe AM, Billinger SA, Gupta A, Hall T, Scheel N, Zhu DC, Hynan LS, Burns JM, Keller JN, Binder EF
JAMA Neurol
· 2026 May · PMID 41870419
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IMPORTANCE: Physical inactivity, hypertension, and hyperlipidemia are modifiable cardiovascular risk factors for age-related cognitive decline and dementia. It remains unknown whether exercise training combined with inte...IMPORTANCE: Physical inactivity, hypertension, and hyperlipidemia are modifiable cardiovascular risk factors for age-related cognitive decline and dementia. It remains unknown whether exercise training combined with intensive pharmacological reduction of cardiovascular risk factors (IRVR) would have greater benefits on cognitive function than those of exercise or IRVR alone. OBJECTIVE: To determine the effects of exercise, IRVR, and exercise combined with IRVR on cognitive function in older adults. DESIGN, SETTING, AND PARTICIPANTS: This single-blind, multicenter randomized clinical trial with a 2 × 2 factorial design and duration of 24 months was conducted at 4 clinical sites in the US. Enrollment began on February 2, 2017; the final study visit was on January 31, 2022. After screening, older adults without dementia and with hypertension, family history of dementia, and/or self-reported subjective cognitive decline were randomized. Data were analyzed from December 2022 through October 2024. INTERVENTIONS: Participants were randomized with a 1:1:1:1 ratio to aerobic exercise training, IRVR (lowering of systolic blood pressure to <130 mm Hg and serum low-density lipoprotein cholesterol with atorvastatin), IRVR + exercise, and usual care. MAIN OUTCOMES AND MEASURES: The primary outcome was change in global cognitive function at 24 months from baseline, assessed with the Preclinical Alzheimer Cognitive Composite (PACC) score. Secondary outcomes were changes in the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) fluid composite score and individual test scores. RESULTS: A total of 3290 individuals were screened, and 513 older adults (aged 60-85 years) without dementia and with hypertension, family history of dementia, and/or self-reported subjective cognitive decline were randomized. Among 513 randomized participants (mean [SD] age, 68.7 [6.0] years; 323 female participants [63.0%]), 443 completed 24-month visits, and 480 were included in the primary data analysis. For the primary outcome, there were no statistically significant interactions between intervention groups and time of visits (P = .13). At 24 months, PACC scores increased by 0.2 units in the no-exercise group (95% CI, 0.1-0.3) and by 0.3 units in the exercise group (95% CI, 0.2-0.4), with no significant group differences (0.1 units; 95% CI, -0.1 to 0.2; P = .37). PACC scores also increased by 0.3 units in the no-IRVR group (95% CI, 0.2-0.4) and by 0.2 units in the IRVR group (95% CI, 0.1-0.3), with no significant group differences (0.1 units; 95% CI, -0.3 to 0.03; P = .12). Increases in the NIHTB-CB composite score and individual test scores with exercise or IRVR showed similar results. CONCLUSIONS AND RELEVANCE: In this multicenter randomized clinical trial among older adults with family history of dementia and/or self-reported subjective cognitive decline, exercise, IRVR, or both did not result in statistically significant differences in improvements in cognitive function over 24 months. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02913664.
Fernandez HH, Isaacson SH, Hauser RA
… +17 more, Agarwal P, Ondo W, Park A, Kremens D, Leoni M, Duvvuri S, Combs C, Koenig E, Chang I, Pastino G, Tringali S, Golonski N, Sanchez R, Harmer L, Boiser J, Zadikoff C, Mari Z
JAMA Neurol
· 2026 May · PMID 41860544
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IMPORTANCE: Development of motor fluctuations is common in people with Parkinson disease (PD) treated with oral levodopa, and currently available dopamine (D) agonists adjunctive to levodopa offer additional motor contro...IMPORTANCE: Development of motor fluctuations is common in people with Parkinson disease (PD) treated with oral levodopa, and currently available dopamine (D) agonists adjunctive to levodopa offer additional motor control but may increase risk of adverse events (AEs) via preferential activation of D2/D3 receptors. Tavapadon is a novel, investigational, oral, once-daily, selective D1/D5 agonist that may improve motor control while minimizing AEs commonly associated with D2/D3 receptor activation. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of tavapadon as adjunctive therapy to oral levodopa in adults with PD experiencing motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: This was a phase 3, double-blind, placebo-controlled randomized clinical trial conducted between September 2020 and February 2024 with a 4-week safety follow-up. Participants were recruited from 148 sites across 14 countries. Participants were enrolled after screening adults with PD who were experiencing fluctuations while receiving stable oral levodopa (≥400 mg daily). INTERVENTIONS: Participants were randomized 1:1 to flexible-dose tavapadon (5-15 mg once daily) or placebo adjunctive to oral levodopa for 27 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline to week 26 in total daily on-time (ie, good mobility, smoother movement, fewer motor/nonmotor symptoms) without troublesome dyskinesia (referred to as good-on-time). The key secondary end point was change from baseline in total daily off-time (ie, return/worsening of motor/nonmotor symptoms often experienced between medication doses). RESULTS: After screening 824 adults with PD, 507 participants (mean [SD] age, 64.9 [8.5] years; 321 male [63%]; mean [SD] disease duration, 6.7 [4.5] years; mean [SD] baseline daily off-time, 5.5 [2.4] hours) were enrolled and received tavapadon (n = 252) or placebo (n = 255). Tavapadon significantly increased daily good-on-time by 1.10 hours compared with placebo (1.70 vs 0.60 hours; 95% CI, 0.60-1.70; P <.001). Daily off-time was significantly reduced from baseline with tavapadon vs placebo (-1.88 vs -0.93 hours; difference, -0.94 hours; 95% CI, -1.48 to -0.41]; P < .001). Tavapadon had a favorable safety profile; although more AEs occurred with tavapadon vs placebo (180 participants [71.7%] vs 140 participants [55.1%]), most were nonserious (93.2%) and mild to moderate in severity. Common AEs with tavapadon (≥5% of participants) were nausea (14.3%), dyskinesia (10.0%), and dizziness (7.6%). CONCLUSIONS AND RELEVANCE: Findings of this randomized clinical trial demonstrate the efficacy, tolerability, and safety profile of tavapadon adjunctive to levodopa for off fluctuations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04542499.
Pahwa R, Moro E, Espay AJ
… +12 more, Evans A, Saint-Hilaire M, Torres-Russotto D, Sanchez R, Leoni M, Duvvuri S, Combs C, Chang I, Tringali S, Boiser J, Zadikoff C, Antonini A
JAMA Neurol
· 2026 May · PMID 41860533
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IMPORTANCE: Tavapadon is an oral, once-daily, selective D1/D5 agonist that may improve Parkinson disease (PD) motor symptoms while minimizing adverse events (AEs) associated with D2/D3 receptor activation. OBJECTIVE: To...IMPORTANCE: Tavapadon is an oral, once-daily, selective D1/D5 agonist that may improve Parkinson disease (PD) motor symptoms while minimizing adverse events (AEs) associated with D2/D3 receptor activation. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of tavapadon in adults with early PD. DESIGN, SETTING, AND PARTICIPANTS: TEMPO-1 was a phase 3, double-blind, placebo-controlled randomized clinical trial conducted at 102 sites across 12 countries between December 2019 and June 2024. Adults with early PD (<3 years' disease duration) who were treatment naive or had less than 3 months of prior dopaminergic treatment were eligible for enrollment. Data analysis was completed from July 2024 to May 2025. INTERVENTION: Participants were randomized 1:1:1 to receive 1 of 2 fixed doses of tavapadon (5 or 15 mg once daily) or placebo for 27 weeks, followed by a 4-week safety follow-up period. MAIN OUTCOMES AND MEASURES: The primary end point was least-squares mean (LSM) change from baseline to week 26 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score. Key secondary end points were LSM change from baseline to week 26 in MDS-UPDRS part II scores and the proportion of participants with a score of "much improved" or "very much improved" on the Patient Global Impression of Change. RESULTS: Overall, 751 adults with early PD who were treatment naive or had less than 3 months of prior dopaminergic treatment were screened, and 529 participants were enrolled (187 female participants [35.3%]; mean [SD] age, 63.7 [9.6] years; mean [SD] disease duration, 0.7 [0.8] years) and randomized to receive tavapadon, 5 mg (n = 177), tavapadon, 15 mg (n = 177), or placebo (n = 175). The change from baseline to week 26 in the MDS-UPDRS parts II and III combined score was significantly improved in participants treated with both the 5-mg dose of tavapadon (9.7-point decrease vs 1.8-point increase with placebo; treatment difference, -11.5 points; 95% CI, -13.8 to -9.2; P < .001; d = 1.14) and 15-mg dose of tavapadon (10.2-point decrease vs 1.8-point increase with placebo; treatment difference, -12.1 points; 95% CI, -14.4 to -9.8; P < .001; d = 1.20). Tavapadon had a favorable safety profile; most AEs were nonserious and mild to moderate in severity. Common AEs with tavapadon were nausea (90 of 354 with tavapadon [25.4%]), headache (59 of 354 [16.7%]), and dizziness (45 of 354 [12.7%]). CONCLUSIONS AND RELEVANCE: In the TEMPO-1 randomized clinical trial, tavapadon improved motor function in participants with early PD and was well tolerated with a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04201093.
Cudkowicz M, Drory VE, Chio A
… +12 more, Lunetta C, Shoesmith C, van Eijk RPA, Salomon-Zimri S, Shtossel D, Kerem N, Shapira G, Shomron N, Russek-Blum N, Tracik F, Rosenfeld J, Shefner J
JAMA Neurol
· 2026 May · PMID 41837970
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IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related m...IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related mechanisms, including neuroinflammation, iron homeostasis, and dysregulated microRNAs. OBJECTIVE: To evaluate the safety, tolerability, and potential efficacy of PrimeC in people living with ALS. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, double-blind, placebo-controlled, phase 2b trial conducted at 4 ALS referral centers from May 2022 to November 2023 and followed by 12-month open-label extension. Adults with definite or probable ALS and disease duration of 30 months or less were eligible. Of 73 screened, 69 were randomized and 68 were included in the intent-to-treat population. INTERVENTIONS: Participants were randomized 2:1 to receive PrimeC or placebo for 6 months, followed by open-label extension PrimeC for all. MAIN OUTCOMES AND MEASURES: The primary outcome was safety and tolerability. The prespecified primary biomarker outcome was plasma neuron-derived-exosomal TAR DNA-binding protein 43 (TDP-43) or prostaglandinJ2. Secondary outcomes included change in ALS Functional Rating Scale-Revised (ALSFRS-R) score at 6 and 18 months, survival, and time-to-composite events. Exploratory biomarkers included neurofilament light chains, iron-regulatory proteins, and circulating microRNAs. RESULTS: The 68 participants were well balanced in age at entry and sex. In the PrimeC group, the mean (SD) age was 59.1 (9.1) years, and 27 of 45 participants were male. In the placebo group, the mean (SD) age was 55.0 (13.0) years, and 14 of 23 participants were male. PrimeC was well tolerated, with a safety profile comparable to placebo (adverse event rate, 66.7% PrimeC vs 65.2% placebo). Drug-related adverse events were more frequent with PrimeC (20.0% vs 4.3%), mostly mild to moderate, and transient. At month 6, the mean ALSFRS-R difference was 2.23 points between PrimeC and placebo (95% CI, -0.61 to 5.07; P = .12). At month 18, ALSFRS-R scores in participants continuously treated with PrimeC maintained a difference (7.92 points; 95% CI, 2.25 to 13.60; P = .007), with significant bulbar difference (3.18 points; 95% CI, 1.32 to 5.04; P = .001). Continuous treatment was associated with lower risk of ALS complications, including hospitalization, respiratory failure, or death (HR, 0.36; 95% CI, 0.15-0.85; P = .02). In the double-blind period, transferrin levels were preserved with PrimeC (1.90 μmol/L difference; P = .03), the negative ferritin-ALSFRS-R correlation observed in placebo (ρ = -0.50; P = .02) was abolished, and ALS-associated microRNAs were downregulated (log2 fold change: miR-199a-3p, -1.87; false discovery rate [FDR] P = .004; miR-199a-5p, -2.23; FDR P < .001; miR-181a-5p: -1.89; FDR P = .001; miR-181b-5p, -1.62; FDR P = .005). Prespecified neuron-derived exosome TDP-43/PgJ2 analyses will be reported separately following completion of development and analyses. CONCLUSIONS AND RELEVANCE: PrimeC was safe and well tolerated over 18 months. Although not powered for efficacy, functional and biomarker findings support a confirmatory trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05357950.
Vietzen H, Kühner LM, Berger SM
… +31 more, Reinecke R, Rostásy K, Saucke H, Kauth F, Koukou G, Sommer S, Wendel EM, Graninger M, Camp JV, Waubant EL, Casper TC, Benson LA, Chitnis T, Aaen GS, Mar S, Weinstock-Guttman B, Lotze TE, Krupp LB, Lassmann H, Weidner L, Pistorius C, Jungbauer C, Ponleitner M, Reindl M, Kornek B, Breu M, Bsteh G, Höftberger R, Berger T, Puchhammer-Stöckl E, Rommer P
JAMA Neurol
· 2026 May · PMID 41801194
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IMPORTANCE: Differentiating multiple sclerosis (MS) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), especially in seronegative cases, remai...IMPORTANCE: Differentiating multiple sclerosis (MS) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), especially in seronegative cases, remains challenging due to overlapping clinical and imaging features. High-level Epstein-Barr virus (EBV)-derived Epstein-Barr nuclear antigen 1 (EBNA-1) peptide antibody titers may be an MS-specific biomarker that could the improve differential diagnosis. OBJECTIVE: To determine whether longitudinal EBNA-1 peptide antibodies can distinguish MS from MOGAD and NMOSD. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, multicenter, longitudinal, case-control study with patients from Austria, Germany, and the US. This study assessed samples from 2 independent retrospective cohorts. A test cohort and a validation cohort assessed longitudinal plasma samples from patients with MS, MOGAD, or NMOSD. Patients were recruited between 2001 and 2023 and followed up for 2 years. A combined analysis of both cohorts was conducted in January 2025. EXPOSURES: Plasma EBNA-1 peptide immunoglobulin G (IgG) titers measured by enzyme-linked immunosorbent assay after diagnosis and in 3 follow-up samples. MAIN OUTCOMES AND MEASURES: Diagnostic utility of persistent EBNA-1 peptide antibody levels across 4 time points in patients with MS compared with patients with MOGAD and NMOSD. RESULTS: This study included the plasma samples of 2091 patients (mean [SD] age, 31.0 [16.9] years; 1137 female [54.4%]) with neuroinflammatory disease and 1976 healthy controls (mean [SD] age, 39.8 [16.2] years; 1120 male [56.7%]) recruited between 2001 and 2023. The test cohort (310 patients; 54.8% female) included 184 patients with MS, 65 with MOGAD, and 61 with NMOSD (including 12 who were seronegative for aquaporin 4 [AQP4] IgG). The validation cohort (183 patients; 126 female [68.8%]) included 142 patients with MS, 24 with MOGAD, and 17 with NMOSD. In the test cohort, 177 patients with MS (96.2%) had high-level titers in 2 or more of 4 follow-up samples compared with 5 patients (7.7%) with MOGAD (odds ratio [OR], 303.4; 95% CI, 94.4-908.6) and 11 patients (18.0%) with NMOSD (OR, 114.9; 95% CI, 43.0-280.0). Among patients with NMOSD who were seronegative for AQP4-IgG, only 1 (11.1%) had persistent high-level EBNA-1 peptide antibody titers compared with 61 matched patients (96.7%) with MS (OR, 236.0; 95% CI, 18.6-2588.0). In the validation cohort, 135 patients (95.1%) with MS had high-level titers in 2 or more of 4 follow-up samples compared with 4 patients (16.7%) with MOGAD (OR, 96.4; 95% CI, 26.6-293.0) and 3 patients (17.6%) with NMOSD (OR, 90.0; 95% CI, 19.7-319.7). CONCLUSIONS AND RELEVANCE: Results of this case-control study reveal that persistent high-level EBNA-1 peptide antibody titers may serve as a reliable biomarker for differentiating MS from MOGAD, and NMOSD.
Barnard SN, French JA, Chen Z
… +13 more, Holmes M, Hegde M, Altalib HH, Winawer M, Sperling M, Jette N, Hope O, Nadkarni S, O'Brien TJ, Kuzniecky R, Lowenstein D, Kanner AM, Human Epilepsy Project Investigators
JAMA Neurol
· 2026 Apr · PMID 41801192
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IMPORTANCE: Psychiatric disturbances are common in epilepsy and are associated with increased risk of premature mortality, lower quality of life, and poor response to antiseizure medications (ASMs). OBJECTIVE: To evaluat...IMPORTANCE: Psychiatric disturbances are common in epilepsy and are associated with increased risk of premature mortality, lower quality of life, and poor response to antiseizure medications (ASMs). OBJECTIVE: To evaluate the role of psychiatric disturbances at the time of epilepsy diagnosis in predicting risk of future treatment resistance in focal epilepsy. DESIGN, SETTING, AND PARTICIPANTS: The Human Epilepsy Project (HEP) is a prospective, observational, international, and multicenter cohort study with follow-up for up to 6 years. Participants with newly diagnosed focal epilepsy, enrolled within 4 months of initiating ASM treatment, between the ages 18 and 60 years, and without significant other comorbidities were recruited during the open period of 2012 to 2020. Data analysis was performed from January to September 2025. EXPOSURE: Presence of a psychiatric diagnosis. MAIN OUTCOMES AND MEASURES: Presence of psychiatric diagnosis (mood/anxiety disorders) measured by Mini International Neuropsychiatric Interview (MINI) and/or suicidality measured by Columbia-Suicide Severity Rating Scale (C-SSRS) at enrollment. Treatment response included the following outcomes: treatment resistant (TR), defined as failure of first 2 adequate ASM trials (ongoing seizures at/above therapeutic doses); treatment sensitive (TS), defined by a minimum period of seizure freedom on first 2 adequate ASM trials (12 months/3-fold greatest pretreatment seizure-free interval, whichever is longer); and indeterminate (neither TR/TS). RESULTS: Of 376 enrolled adults, 347 (median [IQR] age at seizure onset, 33 [23-44] years; 209 female [60.2%]) completed the MINI and C-SSRS at enrollment. Of these individuals, 191 (55%) were TS, 83 (24%) TR, and 73 (21%) indeterminate. The rate of psychiatric disturbance (mood/anxiety disorder; suicidality) at epilepsy diagnosis was 38% (n = 133). Fifty-seven (16%) had mood/anxiety disorder(s) without suicidality, and 75 (22%) expressed suicidality with or without a psychiatric disorder. Suicidality at epilepsy diagnosis was associated with greater than 2-fold risk of developing TR (relative risk [RR], 2.02; 95% CI, 1.32-3.09; P = .001). There were no significant overall associations between mood/anxiety disorders and TR. Suicidality alone significantly increased TR probability from 16.3% (95% CI, 11.3%-21.3%) in those with no psychiatric disturbance to 47.1% (RR, 2.89; 95% CI, 1.65-5.05; P < .001). Anxiety disorder alone increased TR probability to 32.9% (RR, 2.02; 95% CI, 1.10-3.71; P = .02), although this was not statistically significant after correcting for multiple comparisons. There was no significant change in TR probability when mood disorder alone was present; however, presence of mood disorder with suicidality increased TR probability to 39.6% (RR, 2.43; 95% CI, 1.26-4.68; P = .008). CONCLUSIONS AND RELEVANCE: Results of this cohort study reveal that suicidality at the time of focal epilepsy diagnosis was associated with future drug resistance and may be a marker of more severe neuropathology. Psychiatric screening at time of diagnosis may facilitate early identification of patients at risk for treatment refractory epilepsy syndromes.
Kimura K, Nishiyama Y, Iwasaki YK
… +28 more, Shimizu W, Toyoda K, Sakamoto Y, Katano T, Yamamoto T, Takeuchi M, Kumagai K, Tsuto K, Sugi K, Kusano K, Koga M, Okubo S, Sato T, Hamaguchi H, Yoshida A, Kuriki A, Tanno K, Kitagawa K, Hagiwara N, Daida H, Iguchi Y, Fujimoto S, Miyamoto S, Fukuzawa M, Sugimoto M, Takita A, Otsuka T, Okumura K
JAMA Neurol
· 2026 Apr · PMID 41770549
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IMPORTANCE: Among patients with atrial fibrillation, those with a recent stroke are at significantly higher risk of recurrence than those without. Catheter ablation is expected to reduce the risk of recurrent stroke, hea...IMPORTANCE: Among patients with atrial fibrillation, those with a recent stroke are at significantly higher risk of recurrence than those without. Catheter ablation is expected to reduce the risk of recurrent stroke, heart failure, and mortality in these patients. OBJECTIVE: To evaluate the efficacy and safety of catheter ablation added to standard therapy for reducing the risk of recurrent stroke or composite outcomes in patients with atrial fibrillation and a recent history of stroke. DESIGN, SETTING, AND PARTICIPANTS: The Stroke Secondary Prevention With Catheter Ablation and Edoxaban for Patients With Nonvalvular Atrial Fibrillation (STABLED) study was an open-label, parallel-group, randomized clinical trial. Patients were enrolled from January 2018 to March 2021 and observed until March 2024. This study was conducted at 45 sites in Japan. Patients aged 20 years or older and 85 years or younger and those with a definitive diagnosis of nonvalvular atrial fibrillation on electrocardiogram, a history of ischemic stroke, currently receiving or scheduled to receive edoxaban, and having a modified Rankin Scale score of 3 or less were enrolled. Study data were analyzed from September 2024 to July 2025. INTERVENTIONS: Patients were randomized to receive standard therapy or standard therapy plus catheter ablation (after ≥4 weeks of edoxaban, within 1-6 months of index stroke onset). MAIN OUTCOMES AND MEASURES: The primary end point was a composite of recurrent ischemic stroke, systemic embolism, all-cause death, and hospitalization for heart failure. Safety related to the catheter ablation procedure was assessed. RESULTS: A total of 251 patients were enrolled and 249 (mean [SD] age, 71.7 [7.5] years; 187 male [75.1%]) were randomized (standard therapy, 124; standard therapy plus catheter ablation, 125). Median follow-up was greater than 3 years. The primary end point occurred at rates of 4.9% and 5.6% per person-year (hazard ratio, 1.11; 95% CI, 0.62-2.01) with standard therapy vs catheter ablation, respectively. The respective mortality rates were 1.0 and 2.8 per 100 person-years. Two ablation-related adverse events (cardiac tamponade, stroke) were reported (0.8% each). CONCLUSIONS AND RELEVANCE: In patients with atrial fibrillation and a recent stroke history, standard therapy plus catheter ablation did not significantly reduce the risk of the primary composite end point. The observed event rate was lower than anticipated, suggesting that the study was underpowered to detect clinically meaningful differences. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03777631.
Gildengers AG, Ibrahim TS, Anderson SJ
… +14 more, Emanuel JE, Santini T, Diaz JL, Lopresti BJ, Royse SK, Lopez OL, Zeng X, de Almeida B, Alkhateeb SK, Chu C, Karikari TK, Lee L, Weinstein AM, Butters MA
JAMA Neurol
· 2026 Apr · PMID 41770546
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IMPORTANCE: Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium's effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment...IMPORTANCE: Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium's effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment (MCI). OBJECTIVE: To examine the feasibility, safety, and preliminary efficacy of lithium carbonate for delaying cognitive decline in older adults with MCI. DESIGN, SETTING, AND PARTICIPANTS: This single-site, randomized, double-blind, placebo-controlled pilot feasibility clinical trial was conducted at the University of Pittsburgh School of Medicine from February 2018 to August 2024, with 2-year follow-up. Analyses used linear mixed-effects models in the intention-to-treat population. Adults aged 60 years or older with MCI who were free of major psychiatric or neurologic illness and contraindications to lithium were included. Of 170 individuals assessed, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). Data were analyzed from August 2024 to December 2025. INTERVENTION: Daily low-dose lithium carbonate or placebo for 2 years. MAIN OUTCOMES AND MEASURES: Six prespecified coprimary outcomes included cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised, preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor. RESULTS: Among 80 participants (mean [SD] age, lithium: 72.93 [8.77] years; placebo: 71.22 [6.47] years; 56% female), none of the 6 coprimary outcomes met the prespecified significance threshold. Mean (SD) CVLT-II baseline scores were 7.95 (3.4) for lithium and 7.90 (3.9) for placebo; scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Hippocampal and cortical volumes showed a decline over time in both groups, but no significant treatment × time interactions. Serious adverse events occurred in 12 of 41 (29%) receiving lithium vs 9 of 39 (23%) receiving placebo; none were definitely treatment related. One death occurred in the placebo group. Common adverse events included increased creatinine levels (12 of 41 [29%] with lithium vs 12 of 39 [31%] with placebo), diarrhea (12 of 41 [29%] vs 6 of 39 [15%]), tiredness (12 of 41 [29%] vs 6 of 39 [15%]), and tremor occurrence (10 of 41 [24%] vs 6 of 39 [15%]). CONCLUSIONS AND RELEVANCE: This pilot randomized clinical trial established feasibility, confirmed safety and tolerability, and generated effect size estimates for future trials of low-dose lithium in MCI. None of the coprimary outcomes met the prespecified significance threshold. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03185208.